Chronic cocaine abuse remains a considerable public health problem among the nation's adolescent and young adult populations. In addition to the recognized psychosocial burdens associated with cocaine abuse, there are serious physiological consequences that remain poorly understood. Most prominent among the pathophysiological consequences are the cardiovascular toxicities attributed to chronic cocaine use. Myocardial ischemia and infarction and cardiomyopathy remain the most serious cardiovascular consequences of cocaine use in humans and a prominent cause of premature morbidity and mortality among the nation's youth. The fact that many more individuals abuse cocaine than ever develop these cardiovascular complications has suggested that there may be an underlying predisposition to the cardiovascular toxicity of cocaine. Furthermore, whether and to what extent these predisposing factors are genetically or environmentally determined remains a compelling clinical as well as biological question. During the last four years, our laboratory has made several fundamental observations with respect to the cardiovascular responses to cocaine in conscious dogs and non-human primates. Prominent among them is the importance of an intact autonomic nervous system in mediating the cardiovascular responses to cocaine. In addition, we have shown that altered myocardial substrates occur following ventricular denervation or the development of asymptomatic LV dysfunction, enhance the cardiovascular responses to acute cocaine administration. This has lead us to speculate that cardiac dysautonomia may represent an important acquired risk factor for enhanced cardiovascular toxicity following cocaine administration. In this renewal, we will determine the extent to which and the mechanisms whereby chronic cocaine exposure causes LV dysfunction in a conscious pig model. We will demonstrate that chronic cocaine exposure leads to increased myocardial stunning and larger infarct size as well as progressive ventricular dilitation in dilated cardiomyopathy. Finally, we will determine the role of altered SNS activity, altered nitric oxide activity, and increased cytokine expression, in the mechanisms of chronic cocaine toxicity.